Heteroaryl-biphenyl amines for the treatment of PD-L1 diseases

Abstract

Compounds are provided that are useful as immunomodulators. The compounds have the Formula (I) including stereoisomers and pharmaceutically acceptable salts thereof, wherein R 2a , R 2b , R 3 , R 3a , R 4 , R 6 , R 7 , R 8 , A, Z, X 1 and n are as defined herein. Methods associated with preparation and use of such compounds, as well as pharmaceutical compositions comprising such compounds, are also disclosed.

What is claimed is: 
     
       1. A compound of Formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         A is a 5- or 6-membered heteroaryl group which is unsubstituted or substituted with from one to three members independently selected from the group consisting of halogen, C 1-3  alkyl, C 1-3  haloalkyl, C 1-3  alkoxy, OH, and CN; 
         X 1  is a C 1-3  alkylene, which is unsubstituted or substituted with one or two members independently selected from the group consisting of C 1-2  alkyl and CO 2 H; 
         R 2a  and R 2b  are each independently selected from the group consisting of H, C 1-8  alkyl, C 1-8  haloalkyl, —Y, —X 2 —CO 2 R a , —X 2 —OR a , —X 2 —NR a R b , —X 2 —C(O)NR a R b , —X 2 —SO 2 R a , —X 2 —SO 2 NR a R b , —X 2 —SO 3 R a , and —X 2 —Y, wherein each X 2  is a C 1-6  alkylene, and any C 1-8  alkyl or C 1-6  alkylene is unsubstituted or substituted with one or two members independently selected from the group consisting of OH, SO 2 NH 2 , C(O)NH 2 , C(O)NHOH, PO 3 H 2 , CO 2 C 1-8  alkyl, and CO 2 H, and each Y is selected from the group consisting of C 3-6  cycloalkyl, C 4-8  heterocyclyl, and 5- to 6-membered heteroaryl, each of which is unsubstituted or substituted with one to four substituents independently selected from the group consisting of oxo, OH, C 1-4  alkyl, C 1-4  haloalkyl, C 1-4  hydroxyalkyl, C 1-4  alkoxy, C 1-4  haloalkoxy, C 1-4  hydroxyalkoxy, SO 2 NH 2 , C(O)NH 2 , —C(O)NHOH, PO 3 H 2 , CO 2 C 1-8 alkyl, SO 3 H, and CO 2 H; 
         or R 2a  and R 2b  are combined to form a 4- to 9-membered ring or spirocyclic ring, having from zero to two additional heteroatom ring vertices selected from O, N and S;
 wherein the 4- to 9-membered ring or spirocyclic ring formed by combining R 2a  and R 2b  is unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of oxo, C 1-8  alkyl, C 1-8  haloalkyl, C 1-8  hydroxyalkyl, —X 3 —CO 2 R a , —X 3 —OR a , —X 3 —NR a R b , —X 3 —C(O)NR a R b , —X 3 —SO 2 R a , —X 3 —SO 2 NR a R b , and —X 3 —SO 3 R a , wherein X 3  is a bond or C 1-6  alkylene; 
 
         R 3  and R 4  are each independently selected from the group consisting of H, F, Cl, CN, CH 3 , OCH 3 , CH 2 CH 3 , and CF 3 ; 
         the subscript n is 0, 1, 2, or 3; 
         each R 3a  is independently selected from the group consisting of H, F, Cl, C 1-3  alkyl, C 1-3  alkoxy, C 1-3  haloalkyl, C 1-3  haloalkoxy, C 2-3  alkenyl, and CN; 
         R 6 , R 7 , and R 8  are each independently selected from the group consisting of H, F, Cl, CN, CH 3 , OCH 3 , CH 2 CH 3 , and CF 3 ; 
         Z is selected from the group consisting of 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         unsubstituted or substituted with one to three R c ; 
         each R a  is independently selected from the group consisting of H, C 1-6  alkyl, C 3-6  cycloalkyl, C 1-6  haloalkyl, C 1-6  hydroxyalkyl, C 1-6  alkylene-CO 2 H, and C 1-6  alkylene-SO 3 H; 
         each R b  is independently selected from the group consisting of H, C 1-6  alkyl, C 3-6  cycloalkyl, C 1-6  haloalkyl, C 1-6  hydroxyalkyl, C 1-6  alkylene-CO 2 H, and C 1-6  alkylene-SO 3 H, each of which is unsubstituted or substituted with one or two members independently selected from OH, SO 2 NH 2 , C(O)NH 2 , C(O)NHOH, PO 3 H 2 , CO 2 C 1-8  alkyl, and CO 2 H; 
         and R a  and R b , when attached to the same nitrogen atom, are optionally combined to form a 4- to 8-membered ring or spirocyclic ring, which is unsubstituted or substituted with halogen, OH, SO 2 NH 2 , C(O)NH 2 , C(O)NHOH, PO 3 H 2 , CO 2 C 1-8  alkyl, or —CO 2 H; and 
         each R c  is independently selected from the group consisting of H, halogen, CN, C 1-6  alkyl, C 1-6  haloalkyl, —Y 1 , —X 4 —CO 2 R a , —O—X 4 —CO 2 R a , —X 4 —OR a , —X 4 —NR a R b , —X 4 —C(O)NR a R b , —O—X 4 —C(O)NR a R b , —X 4 —SO 2 R a , —X 4 —SO 2 NR a R b , —X 4 —SO 3 R a , and —N(R a )—X 4 —CO 2 R a , wherein each X 4  is a bond or C 1-6  alkylene, and each Y 1  is independently selected from the group consisting of C 3-6  cycloalkyl and C 4-8  heterocyclyl; and optionally two R c  on adjacent ring vertices are combined to form a fused 5- or 6-membered heterocyclic ring. 
       
     
     
       2. A compound of Formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         A is a 5- or 6-membered heteroaryl group which is unsubstituted or substituted with from one or two members independently selected from the group consisting of halogen, C 1-3  alkyl, C 1-3  haloalkyl, C 1-3  alkoxy, and CN; 
         X 1  is a C 1-3  alkylene, which is unsubstituted or substituted with one or two members independently selected from the group consisting of C 1-2  alkyl and CO 2 H; 
         R 2a  and R 2b  are each independently selected from the group consisting of H, C 1-8  alkyl, C 1-8  haloalkyl, —Y, —X 2 —CO 2 R a , —X 2 —OR a , —X 2 —NR a R b , —X 2 —C(O)NR a R b , —X 2 —SO 2 R a , —X 2 —SO 2 NR a R b , —X 2 —SO 3 R a , and —X 2 —Y, wherein each X 2  is a C 1-6  alkylene, and any C 1-8  alkyl or C 1-6  alkylene is unsubstituted or substituted with one or two members independently selected from the group consisting of OH, SO 2 NH 2 , C(O)NH 2 , C(O)NHOH, PO 3 H 2 , CO 2 C 1-8  alkyl, and CO 2 H, and each Y is selected from the group consisting of C 3-6  cycloalkyl, C 4-8  heterocyclyl, and 5- to 6-membered heteroaryl, each of which is unsubstituted or substituted with one to four substituents independently selected from the group consisting of oxo, OH, C 1-4  alkyl, C 1-4  haloalkyl, C 1-4  hydroxyalkyl, C 1-4  alkoxy, C 1-4  haloalkoxy, C 1-4  hydroxyalkoxy, SO 2 NH 2 , C(O)NH 2 , C(O)NHOH, PO 3 H 2 , CO 2 C 1-8  alkyl, SO 3 H, and CO 2 H; 
         or R 2a  and R 2b  are combined to form a 4- to 9-membered ring or spirocyclic ring, having from zero to two additional heteroatom ring vertices selected from O, N, and S;
 wherein the 4- to 9-membered ring or spirocyclic ring formed by combining R 2a  and R 2b  is unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of oxo, C 1-8  alkyl, C 1-8  haloalkyl, C 1-8  hydroxyalkyl, —X 3 —CO 2 R a , —X 3 —OR a , —X 3 —NR a R b , —X 3 —C(O)NR a R b , —X 3 —SO 2 R a , —X 3 —SO 2 NR a R b , and —X 3 —SO 3 R a , wherein X 3  is a bond or C 1-6  alkylene; 
 
         R 3  and R 4  are each independently selected from the group consisting of F, C 1 , CN, CH 3 , OCH 3 , CH 2 CH 3 , and CF 3 ; 
         the subscript n is 0, 1, 2, or 3; 
         each R 3a  is independently selected from the group consisting of H, F, C 1 , C 1-3  alkyl, C 1-3  alkoxy, C 1-3  haloalkyl, C 1-3  haloalkoxy, C 2-3  alkenyl, and CN; 
         R 6 , R 7 , and R 8  are each independently selected from the group consisting of H, F, C 1 , CN, CH 3 , OCH 3 , CH 2 CH 3 , and CF 3 ; 
         Z is selected from the group consisting of 
       
       
         
           
           
               
               
           
         
         unsubstituted or substituted with one to three R c ; 
         each R a  is independently selected from the group consisting of H, C 1-6  alkyl, C 3-6  cycloalkyl, C 1-6  haloalkyl, C 1-6  hydroxyalkyl, C 1-6  alkylene-CO 2 H, and C 1-6  alkylene-SO 3 H; 
         each R b  is independently selected from the group consisting of H, C 1-6  alkyl, C 3-6  cycloalkyl, C 1-6  haloalkyl, C 1-6  hydroxyalkyl, C 1-6  alkylene-CO 2 H, and C 1-6  alkylene-SO 3 H, each of which is unsubstituted or substituted with one or two members independently selected from OH, SO 2 NH 2 , C(O)NH 2 , C(O)NHOH, PO 3 H 2 , C 02 C 1-8  alkyl, and —CO 2 H; 
         and R a  and R b , when attached to the same nitrogen atom, are optionally combined to form a 4- to 8-membered ring or spirocyclic ring, which is unsubstituted or substituted with halogen, OH, SO 2 NH 2 , C(O)NH 2 , C(O)NHOH, PO 3 H 2 , C 02 C 1-8  alkyl, or CO 2 H; and 
         each R c  is independently selected from the group consisting of H, halogen, CN, C 1-6  alkyl, C 1-6  haloalkyl, —Y 1 , —X 4 —CO 2 R a , —O—X 4 —CO 2 R a , —X 4 —OR a , —X 4 —NR a R b , —X 4 —C(O)NR a R b , —O—X 4 —C(O)NR a R b , —X 4 —SO 2 R a , —X 4 —SO 2 NR a R b , —X 4 —SO 3 R a , and —N(R a )—X 4 —CO 2 R a , wherein each X 4  is a bond or C 1-6  alkylene, and each Y 1  is independently selected from the group consisting of C 3-6  cycloalkyl and C 4-8  heterocyclyl; and optionally two R c  on adjacent ring vertices are combined to form a fused 5- or 6-membered heterocyclic ring. 
       
     
     
       3. The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, having formula (Ia): 
       
         
           
           
               
               
           
         
       
     
     
       4. The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is a 6-membered heteroaryl group which is unsubstituted or substituted with from one to three members independently selected from the group consisting of halogen, C 1-3  alkyl, C 1-3  haloalkyl, C 1-3  alkoxy, OH, and CN. 
     
     
       5. The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, having formula (Ib): 
       
         
           
           
               
               
           
         
       
     
     
       6. The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is unsubstituted or substituted with one or two members independently selected from the group consisting of CF 3 , OH, Et, CN, OCH 3 , and F. 
     
     
       7. The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is a 6-membered heteroaryl group selected from the group consisting of pyridine, pyrimidine, pyrazine, and 1,2,4-triazine, each of which is unsubstituted or substituted with one or two members independently selected from the group consisting of CF 3 , OH, Et, CN, OCH 3 , and F. 
     
     
       8. The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein —N(R 2a )(R 2b ) is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
       9. The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein —N(R 2a )(R 2b ) is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
       10. The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein —N(R 2a )(R 2b ) is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
       11. The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y is selected from the group consisting of C 3-6  cycloalkyl and C 4-8  heterocyclyl, each of which is unsubstituted or substituted with one to four substituents independently selected from the group consisting of oxo, OH, C 1-4  alkyl, C 1-4 haloalkyl, C 1-4  hydroxyalkyl, C 1-4  alkoxy, C 1-4  haloalkoxy, C 1-4  hydroxyalkoxy, SO 2 NH 2 , C(O)NH 2 , C(O)NHOH, PO 3 H 2 , CO 2 C 1-8  alkyl, SO 3 H and CO 2 H. 
     
     
       12. The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, oxazolyl, thiazolyl, and pyrazolyl, each of which is unsubstituted or substituted with one or two members independently selected from the group consisting of halogen, C 1-3  alkyl, C 1-3  haloalkyl, C 1-3  alkoxy, OH, and CN. 
     
     
       13. The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein Z is a 
       
         
           
           
               
               
           
         
         unsubstituted or substituted by one to three R c , wherein each R c  is independently selected from the group consisting of halogen, C 1-6  alkyl, and C 1-6  haloalkyl. 
       
     
     
       14. The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein Z is a 
       
         
           
           
               
               
           
         
         unsubstituted or substituted by one to three R c , wherein each R c  is independently selected from the group consisting of halogen, C 1-6  alkyl, and C 1-6  haloalkyl. 
       
     
     
       15. The compound of  claim 5 , or a pharmaceutically acceptable salt thereof, wherein:
 A is a 6-membered heteroaryl group which is unsubstituted or substituted with from one to three members independently selected from the group consisting of halogen, C 1-3  alkyl, C 1-3  haloalkyl, C 1-3  alkoxy, OH, and CN; and 
 Z is a 
 
       
         
           
           
               
               
           
         
         
           unsubstituted or substituted by one to three R c , wherein each R c  is independently selected from the group consisting of halogen, C 1-6  alkyl, and C 1-6  haloalkyl. 
         
       
     
     
       16. The compound of  claim 15 , or a pharmaceutically acceptable salt thereof, wherein A is selected from the group consisting of pyridinyl, pyrimidinyl, and pyrazinyl, each of which is unsubstituted or substituted with one or two members independently selected from the group consisting of halogen, C 1-3  alkyl, C 1-3  haloalkyl, C 1-3  alkoxy, and CN. 
     
     
       17. The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is an optically pure or enriched isomer. 
     
     
       18. The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
       19. The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
       20. The compound of  claim 1 , which is 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
       21. The compound of  claim 1 , which is 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
       22. The compound of  claim 1 , which is 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
       23. The compound of  claim 1 , which is 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
       24. The compound of  claim 1 , which is 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
       25. The compound of  claim 1 , which is 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
       26. A pharmaceutical composition comprising a compound of  claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.